Growing evidence suggests that pathways in addition to innaraination and dyslipidemia contribute tothe undtsrlyiiig processes of atherosclen3sis;endathelial dysfunction, a Howcvcr,:,fGw studies liave examined tlielhterreiatioiis between oxidative istressj.endiottielial dysfui!(:l;ian,:and; CHD. Asymmetric dimethylarginlne (ADMA) Is an endogenous inliibitor of nitricoxidesynthase (NOS), anti has recently emerged p a potential novel risk mpt^ker iiietabolizedljy the enzyme, dimethylarginine diraethylaminohydrolase (DDAiHI), and increa stress inhibit DDAH activity in the tissues, which leads to sustained levels of ADMA. Accumulatipri ofADMA and reduced NO synthesis leads coendothellalciysfunction and also initiates and promoteiu processes involved with atherogenesis. Plasrha ADMA levels have been associated with several risk factors oif GHD;however, data on the predictive valite of ADMA, genetic variation iii the DDAH giene, arid the prospective risk of CHD in men and women have th its far been limited;The goal of this proposal is to irtvestigate plasma ADMA: levels as a novel biochemical predictor of CilD among tyvo large prospective cohort studies: the NufsCLs'Health Study (NHS) and the Health Professionals Foliow-up Study (HPFS). Both studies have over 22 years of repeated dietary and lifestyle questionnaire data, blood samples collected from 32,826'wonVen in NHf and,l,:8,225:men in HPFS, and nested case-control studies with biologiical specimens previously archived among Incident cases of nonfaial mypcardialinfari:tion or fatal CHD, and/age and smoking thatched conti"ols. The specific aims of this prpposal are to;!;) exaniihe^the'prospective relationship between plasma ADM control settings among men and womeri;2.):UtiIlze the existing prospective data toexamine inteiTelations betvveen lifestylts^tlietai-y, arid other hiealth faCtoi-s,;and plasma ADMA to elueidale potential;mechanistris;and 3.) examine the.genetic variation in the DDAH gene with plasma ADMA levels and risk bf.GHD in both men and women. These findings may lead to new therapeutic interventions vvhich inhibltthe effects of ADMA arid prevent che progression df atherosclerosis and cardiovascular disease.